Genetic Phenomena Commons^™

Anatomy And Function Of Ventral Tegmental Area Glutamate Neurons, Jing Cai, Qingchun Tong

Faculty, Staff and Student Publications

The ventral tegmental area (VTA) is well known for regulating reward consumption, learning, memory, and addiction behaviors through mediating dopamine (DA) release in downstream regions. Other than DA neurons, the VTA is known to be heterogeneous and contains other types of neurons, including glutamate neurons. In contrast to the well-studied and established functions of DA neurons, the role of VTA glutamate neurons is understudied, presumably due to their relatively small quantity and a lack of effective means to study them. Yet, emerging studies have begun to reveal the importance of glutamate release from VTA neurons in regulating diverse behavioral repertoire …

Use Of The Fully Spectroscopic Pixelated Cadmium Telluride Detector For Benchtop X-Ray Fluorescence Computed Tomography, Sandun Jayarathna, Hem Moktan, Sang Hyun Cho

Faculty, Staff and Student Publications

In this work, we integrated a commercially-available fully-spectroscopic pixelated cadmium telluride (CdTe) detector system as a two-dimensional (2D) array detector into our existing benchtop cone-beam x-ray fluorescence computed tomography (XFCT) system. After integrating this detector, known as High-Energy X-ray Imaging Technology (HEXITEC), we performed quantitative imaging of gold nanoparticle (GNP) distribution in a small animal-sized phantom using our benchtop XFCT system. Owing to the upgraded detector component within our benchtop XFCT system, we were able to conduct this phantom imaging in an unprecedented manner by volumetric XFCT scans followed by XFCT image reconstruction in 3D. The current results showed that …

Cgas-Sting Pathway Targeted Therapies And Their Applications In The Treatment Of High-Grade Glioma, Shashwat Tripathi, Hinda Najem, Akanksha Sanjay Mahajan, Peng Zhang, Justin T Low, Alexander H Stegh, Michael A Curran, David M Ashley, Charles David James, Amy B Heimberger

Faculty, Staff and Student Publications

Median survival of patients with glioblastoma (GBM) treated with standard of care which consists of maximal safe resection of the contrast-enhancing portion of the tumor followed by radiation therapy with concomitant adjuvant temozolomide (TMZ) remains 15 months. The tumor microenvironment (TME) is known to contain immune suppressive myeloid cells with minimal effector T cell infiltration. Stimulator of interferon genes (STING) is an important activator of immune response and results in production of Type 1 interferon and antigen presentation by myeloid cells. This review will discuss important developments in STING agonists, potential biomarkers for STING response, and new combinatorial therapeutic approaches …

Behavioural Immune Landscapes Of Inflammation, Georgiana Crainiciuc, Miguel Palomino-Segura, Miguel Molina-Moreno, Jon Sicilia, David G Aragones, Jackson Liang Yao Li, Rodrigo Madurga, José M Adrover, Alejandra Aroca-Crevillén, Sandra Martin-Salamanca, Alfonso Serrano Del Valle, Sandra D Castillo, Heidi C E Welch, Oliver Soehnlein, Mariona Graupera, Fátima Sánchez-Cabo, Alexander Zarbock, Thomas E Smithgall, Mauro Di Pilato, Thorsten R Mempel, Pierre-Louis Tharaux, Santiago F González, Angel Ayuso-Sacido, Lai Guan Ng, Gabriel F Calvo, Iván González-Díaz, Fernando Díaz-De-María, Andrés Hidalgo

Faculty, Staff and Student Publications

Transcriptional and proteomic profiling of individual cells have revolutionized interpretation of biological phenomena by providing cellular landscapes of healthy and diseased tissues1,2. These approaches, however, do not describe dynamic scenarios in which cells continuously change their biochemical properties and downstream 'behavioural' outputs3-5. Here we used 4D live imaging to record tens to hundreds of morpho-kinetic parameters describing the dynamics of individual leukocytes at sites of active inflammation. By analysing more than 100,000 reconstructions of cell shapes and tracks over time, we obtained behavioural descriptors of individual cells and used these high-dimensional datasets to build behavioural landscapes. These landscapes recognized leukocyte …

Screening Of Hydrocarbon-Stapled Peptides For Inhibition Of Calcium-Triggered Exocytosis, Ying Lai, Michael J Tuvim, Jeremy Leitz, John Peters, Richard A Pfuetzner, Luis Esquivies, Qiangjun Zhou, Barbara Czako, Jason B Cross, Philip Jones, Burton F Dickey, Axel T Brunger

Faculty, Staff and Student Publications

The so-called primary interface between the SNARE complex and synaptotagmin-1 (Syt1) is essential for Ca2+-triggered neurotransmitter release in neuronal synapses. The interacting residues of the primary interface are conserved across different species for synaptotagmins (Syt1, Syt2, Syt9), SNAP-25, and syntaxin-1A homologs involved in fast synchronous release. This Ca2+-independent interface forms prior to Ca2+-triggering and plays a role in synaptic vesicle priming. This primary interface is also conserved in the fusion machinery that is responsible for mucin granule membrane fusion. Ca2+-stimulated mucin secretion is mediated by the SNAREs syntaxin-3, SNAP-23, VAMP8, Syt2, and other proteins. Here, we designed and screened a …

Advancing The Standard: Venetoclax Combined With Intensive Induction And Consolidation Therapy For Acute Myeloid Leukemia, Curtis A Lachowiez, Himachandana Atluri, Courtney D Dinardo

Faculty, Staff and Student Publications

The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (VEN) in combination with lower-intensity therapy is an efficacious treatment for acute myeloid leukemia (AML). VEN in combination with the hypomethylating agent azacitidine improved rates of response and measurable residual disease (MRD)-negative remissions in addition to overall survival in the pivotal phase 3 VIALE-A trial compared with azacitidine monotherapy and has since emerged as the current standard of care in older or unfit patients with AML. In younger, fit patients with AML, intensive induction and consolidation chemotherapy (IC) is commonly employed as frontline therapy; however, relapse remains the principal cause of treatment failure …

Prediction Of Early (4-Week) Mortality In Acute Myeloid Leukemia With Intensive Chemotherapy, Koji Sasaki, Tapan Kadia, Kebede Begna, Courtney D Dinardo, Gautam Borthakur, Nicholas J Short, Nitin Jain, Naval Daver, Elias Jabbour, Guillermo Garcia-Manero, Guillermo Montalban Bravo, Lucia Masarova, Sherry Pierce, Marina Konopleva, Farhad Ravandi, Ayalew Tefferi, Hagop Kantarjian

Faculty, Staff and Student Publications

The progress with intensive chemotherapy and supportive care measures has improved survival in patients with newly diagnosed acute myeloid leukemia (AML). Given the recent development of effective low intensity therapies, an optimal decision on the therapy intensity may improve survival through the avoidance of early mortality. We reviewed the outcome of 3728 patients with newly diagnosed AML who received intensive chemotherapy between August 1980 and May 2020. Intensive chemotherapy was defined as a cumulative cytarabine dose ≥ 700 mg/m2 during induction therapy. We divided the whole cohort into a training and validation group at a 3:1 ratio. The population was …

Surgical Management Of Brain Metastasis: Challenges And Nuances, Chibawanye I Ene, Sherise D Ferguson

Faculty, Staff and Student Publications

Brain metastasis is the most common type of intracranial tumor. The contemporary management of brain metastasis is a challenging issue and traditionally has carried a poor prognosis as these lesions typically occur in the setting of advanced cancer. However, improvement in systemic therapy, advances in radiation techniques and multimodal therapy tailored to the individual patient, has given hope to this patient population. Surgical resection has a well-established role in the management of brain metastasis. Here we discuss the evolving role of surgery in the treatment of this diverse patient population.

The Seen And The Unseen: Molecular Classification And Image Based-Analysis Of Gastrointestinal Cancers, Corina-Elena Minciuna, Mihai Tanase, Teodora Ecaterina Manuc, Stefan Tudor, Vlad Herlea, Mihnea P Dragomir, George A Calin, Catalin Vasilescu

Faculty, Staff and Student Publications

Gastrointestinal cancers account for 22.5% of cancer related deaths worldwide and represent circa 20% of all cancers. In the last decades, we have witnessed a shift from histology-based to molecular-based classifications using genomic, epigenomic, and transcriptomic data. The molecular based classification revealed new prognostic markers and may aid the therapy selection. Because of the high-costs to perform a molecular classification, in recent years immunohistochemistry-based surrogate classification were developed which permit the stratification of patients, and in parallel multiple groups developed hematoxylin and eosin whole slide image analysis for sub-classifying these entities. Hence, we are witnessing a return to an image-based …

Translating Mentoring Interventions Research Into Practice: Evaluation Of An Evidence-Based Workshop For Research Mentors On Developing Trainees’ Scientific Communication Skills, Erin K Dahlstrom, Christine Bell, Shine Chang, Hwa Young Lee, Cheryl B Anderson, Annie Pham, Christine Maidl Pribbenow, Carrie A Cameron

Faculty, Staff and Student Publications

A key part of keeping doctoral and postdoctoral trainees in STEM research careers is mentoring. Our previous research indicates that mentoring trainees in scientific communication (SC) skill development increases research career intention through two social-cognitive constructs, self-efficacy in and outcome expectations for acquiring SC skills, as well as science identity. While many mentor training interventions exist, no programs focus on developing SC skills specifically. The "Scientific Communication Advances Research Excellence" (SCOARE) program trains mentors to address trainee scientific communication (SC) skill development as an innovative approach to increase trainee research career persistence. The SCOARE training is a half-day workshop for …

A Narrative Review On Invasive Brain Stimulation For Treatment-Resistant Depression, Manoj P Dandekar, Alexandre P Diaz, Ziaur Rahman, Ritele H Silva, Ziad Nahas, Scott Aaronson, Sudhakar Selvaraj, Albert J Fenoy, Marsal Sanches, Jair C Soares, Patricio Riva-Posse, Joao Quevedo

Faculty, Staff and Student Publications

While most patients with depression respond to pharmacotherapy and psychotherapy, about one-third will present treatment resistance to these interventions. For patients with treatment-resistant depression (TRD), invasive neurostimulation therapies such as vagus nerve stimulation, deep brain stimulation, and epidural cortical stimulation may be considered. We performed a narrative review of the published literature to identify papers discussing clinical studies with invasive neurostimulation therapies for TRD. After a database search and title and abstract screening, relevant English-language articles were analyzed. Vagus nerve stimulation, approved by the U.S. Food and Drug Administration as a TRD treatment, may take several months to show therapeutic …

Evaluating A Pilot Culturally Sensitive Psychosocial Intervention On Posttraumatic Growth For Chinese American Breast Cancer Survivors, Qiao Chu, Moni Tang, Lingjun Chen, Lucy Young, Alice Loh, Carol Wang, Qian Lu

Faculty, Staff and Student Publications

This study investigated the potential benefit of a pilot culturally sensitive group support intervention, named Joy Luck Academy (JLA), in fostering posttraumatic growth among Chinese American breast cancer survivors. Eighty-six Chinese American breast cancer survivors participated in an eight-week single-arm pre-/post-test trial of an intervention program, which included educational lectures and peer mentor support. The JLA participants were compared with an independent sample of 109 Chinese American breast cancer survivors who went through routine care. Both groups completed baseline and eight-week follow-up assessments of the five facets of posttraumatic growth (meaningful interpersonal relationships, finding new possibilities in life, personal strength, …

Quaking But Not Parkin Is The Major Tumor Suppressor In 6q Deleted Region In Glioblastoma, Fatma Betul Aksoy Yasar, Takashi Shingu, Daniel B Zamler, Mohammad Fayyad Zaman, Derek Lin Chien, Qiang Zhang, Jiangong Ren, Jian Hu

Faculty, Staff and Student Publications

Glioblastoma (GBM) is a high-grade, aggressive brain tumor with dismal median survival time of 15 months. Chromosome 6q (Ch6q) is a hotspot of genomic alterations, which is commonly deleted or hyper-methylated in GBM. Two neighboring genes in this region, QKI and PRKN have been appointed as tumor suppressors in GBM. While a genetically modified mouse model (GEMM) of GBM has been successfully generated with Qk deletion in the central nervous system (CNS), in vivo genetic evidence supporting the tumor suppressor function of Prkn has not been established. In the present study, we generated a mouse model with Prkn-null allele …

Update On Mri In Evaluation And Treatment Of Endometrial Cancer, Ekta Maheshwari, Stephanie Nougaret, Erica B Stein, Gaiane M Rauch, Ken-Pin Hwang, R Jason Stafford, Ann H Klopp, Pamela T Soliman, Katherine E Maturen, Andrea G Rockall, Susanna I Lee, Elizabeth A Sadowski, Aradhana M Venkatesan

Faculty, Staff and Student Publications

Endometrial cancer is the second most common gynecologic cancer worldwide and the most common gynecologic cancer in the United States, with an increasing incidence in high-income countries. Although the International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial cancer is a surgical staging system, contemporary published evidence-based data and expert opinions recommend MRI for treatment planning as it provides critical diagnostic information on tumor size and depth, extent of myometrial and cervical invasion, extrauterine extent, and lymph node status, all of which are essential in choosing the most appropriate therapy. Multiparametric MRI using a combination of T2-weighted sequences, …

Loss Of Mmr And Tgfbr2 Increases The Susceptibility To Microbiota-Dependent Inflammation-Associated Colon Cancer, Elena Tosti, Ana S Almeida, Tam T T Tran, Mariel Barbachan E Silva, Pilib Ó Broin, Robert Dubin, Ken Chen, Amanda P Beck, Andrew S Mclellan, Eduardo Vilar, Aaron Golden, Paul W O'Toole, Winfried Edelmann

Faculty, Staff and Student Publications

Background and aims: Mutations in DNA mismatch repair (MMR) genes are causative in Lynch syndrome and a significant proportion of sporadic colorectal cancers (CRCs). MMR-deficient (dMMR) CRCs display increased mutation rates, with mutations frequently accumulating at short repetitive DNA sequences throughout the genome (microsatellite instability). The TGFBR2 gene is one of the most frequently mutated genes in dMMR CRCs. Therefore, we generated an animal model to study how the loss of both TGFBR2 signaling impacts dMMR-driven intestinal tumorigenesis in vivo and explore the impact of the gut microbiota.

Methods: We generated VCMsh2/Tgfbr2 mice in which Msh2loxP and Tgfbr2loxP alleles are …

Recent Advances On Dna Base Flipping: A General Mechanism For Writing, Reading, And Erasing Dna Modifications, Ren Ren, John R Horton, Samuel Hong, Xiaodong Cheng

Faculty, Staff and Student Publications

The modification of DNA bases is a classic hallmark of epigenetics. Four forms of modified cytosine-5-methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine-have been discovered in eukaryotic DNA. In addition to cytosine carbon-5 modifications, cytosine and adenine methylated in the exocyclic amine-N4-methylcytosine and N6-methyladenine-are other modified DNA bases discovered even earlier. Each modified base can be considered a distinct epigenetic signal with broader biological implications beyond simple chemical changes. Since 1994, several crystal structures of proteins and enzymes involved in writing, reading, and erasing modified bases have become available. Here, we present a structural synopsis of writers, readers, and erasers of the modified …

A Phase I, Open-Label, Dose-Escalation Study Of The Ox40 Agonist Ivuxolimab In Patients With Locally Advanced Or Metastatic Cancers, Adi Diab, Omid Hamid, John A Thompson, Willeke Ros, Ferry A L M Eskens, Toshihiko Doi, Siwen Hu-Lieskovan, Samuel J Klempner, Bishu Ganguly, Catherine Fleener, Xiao Wang, Tenshang Joh, Ken Liao, Shahram Salek-Ardakani, Carrie Turich Taylor, Jeffrey Chou, Anthony B El-Khoueiry

Faculty, Staff and Student Publications

PURPOSE: Stimulation of effector T cells is an appealing immunotherapeutic approach in oncology. OX40 (CD134) is a costimulatory receptor expressed on activated CD4

PATIENTS AND METHODS: Adult patients (

RESULTS: The most common all-causality adverse events were fatigue (46.2%), nausea (28.8%), and decreased appetite (25.0%). Of 31 treatment-related adverse events, 30 (96.8%) were grade ≤2. No dose-limiting toxicities occurred. Ivuxolimab exposure increased in a dose-proportionate manner from 0.3 to 10 mg/kg. Full peripheral blood target engagement occurred at ≥0.3 mg/kg. Three (5.8%) patients achieved a partial response, and disease control was achieved in 56% of patients. Increased CD4

CONCLUSIONS: Ivuxolimab …

Inhibition Of The Cd47-Sirpα Axis For Cancer Therapy: A Systematic Review And Meta-Analysis Of Emerging Clinical Data, Ji Son, Rodney Cheng-En Hsieh, Heather Y Lin, Kate J Krause, Ying Yuan, Amadeo B Biter, James Welsh, Michael A Curran, David S Hong

Faculty, Staff and Student Publications

CD47-SIRPα interaction acts as a "don't eat me" signal and is exploited by cancer to downregulate innate and adaptive immune surveillance. There has been intense interest to develop a mechanism of blockade, and we aimed to analyze the emerging data from early clinical trials. We performed a systematic review and meta-analysis of relevant databases and conference abstracts including clinical trials using CD47 and/or SIRPα inhibitors in cancer treatment. Nonlinear mixed models were applied for comparison of response and toxicity. We retrieved 317 articles, 24 of which were eligible. These included 771 response-evaluable patients with hematologic (47.1%) and solid tumors (52.9%). …

Cell-Directed Aptamer Therapeutic Targeting For Cancers Including Those Within The Central Nervous System, Jun Wei, Renduo Song, Aria Sabbagh, Anantha Marisetty, Neal Shukla, Dexing Fang, Hinda Najem, Martina Ott, James Long, Lijie Zhai, Maciej S Lesniak, Charles David James, Leonidas Platanias, Michael Curran, Amy B Heimberger

Faculty, Staff and Student Publications

Osteopontin (OPN) is produced by tumor cells as well as by myeloid cells and is enriched in the tumor microenvironment (TME) of many cancers. Given the roles of OPN in tumor progression and immune suppression, we hypothesized that targeting OPN with aptamers that have high affinity and specificity could be a promising therapeutic strategy. Bi-specific aptamers targeting ligands for cellular internalization were conjugated to siRNAs to suppress OPN were created, and therapeutic leads were selected based on target engagement and

Comparison Of Psma-Based 18f-Dcfpyl Pet/Ct And Pelvic Multiparametric Mri For Lesion Detection In The Pelvis In Patients With Prostate Cancer, Trinh T Nguyen, Priya R Bhosale, Guofan Xu, Tinsu Pan, Peng Wei, Yang Lu

Faculty, Staff and Student Publications

Purpose: To directly compare the performance of pelvic mpMRI versus recently approved and increasingly used PSMA-based 18F-DCFPyL PET/CT in intermediate-high risk and biochemical recurrent prostate cancer patient cohort while exploring their potential differing applications in specific clinical scenarios.

Methods: A retrospective analysis was performed on patients who had 18F-DCFPyL PET/CT and pelvic mpMRI done from September 2021 to January 2022 at a single institution. The inclusion criteria were paired exams within a 3-month interval. Exclusion criteria were intervening treatment between exams, a change in PSA by more than 50% and absolute difference more than 1 ng/mL, or concurrent history of …